Photobiomodulation, using light emitting diode (LEDs) arrays or low energy lasers, has been reported to have a variety of therapeutic benefits (Conlan et al. 1996; Sommer et al. 2001; Whelan et al. 2001; Yu et al. 1997; Delellis et al. 2005; Powell et al. 2004; Harkless et al. 2006; Powell et al. 2006). This non-invasive therapy has been used to accelerate wound healing, improve recovery rates from ischemia, slow degeneration of injured optic nerves, and improve sensitivity and reduce pain in various types of peripheral neuropathies including those associated with diabetes.
Diabetes is a common metabolic disorder that is rapidly becoming an epidemic worldwide (Lowell and Schulman, 2005). In the United States, Type II diabetes is the leading cause of blindness. Diabetic peripheral neuropathies are some of the most common long-term complications of diabetes (Pop-Busui et al. 2006). They are a major cause of pain associated with diabetes and often result in lower extremity amputations. Although studies have reported that many patients with diabetic peripheral neuropathies are responsive to near infrared radiation (NIR) therapy (Delellis et al. 2004; Powell et al. 2004; Harkless et al. 2006; Powell et al. 2006) the therapeutic mode of action of photobiomodulation in treating these neuropathies is not yet clear.
NIR is effective in these therapies. Light in the NIR has significant advantages over visible or ultraviolet light because it penetrates tissues more deeply than visible light and at the same time lacks the carcinogenic and mutagenic properties of ultraviolet light (Whelan et al., 2001, 2002). The cellular and molecular mechanisms that underlie the therapeutic benefits of NIR are still poorly understood. However, several studies have revealed that the most effective wavelengths for therapeutic photobiomodulation are between 600 and 830 nm (Karu, 1999; Karu, 2005).
Until recently, mitochondrial cytochrome c oxidase was thought to have only one enzymatic activity; the reduction of oxygen to water. This reaction occurs under normoxic conditions and involves the addition of 4 electrons and 4 protons to diatomic oxygen. During this process oxygen is reduced by a series of one electron transfers. The first electron added to oxygen produces superoxide (O2−), the second electron produces peroxide (H2O2), the third electron added produces the hydroxyl ion (OH−), and the fourth electron produces water. Superoxide, hydrogen peroxide, and the hydroxyl ion are incompletely reduced forms of oxygen and are referred to collectively as reactive oxygen species (ROS). ROS are normally sequestered at the binuclear reaction center within the holocytochrome c oxidase molecule and are not released. However, under some pathological conditions (Poyton, 1999) they are released and can either act destructively (to induce oxidative stress, a condition that lies at the heart of many diseases as well as aging), or constructively (in intracellular signaling pathways (Poyton and McEwen, 1996)). Because light can affect the oxidation state of cytochrome c oxidase (Winterrle and Einarsdottir, 2006, Tachtsidis et al. 2007) it can also alter the conformation of the binuclear reaction center and cause the release of reactive oxygen species.
It is now clear that the mitochondrial respiratory chain and mitochondrial cytochrome c oxidase can have profound effects on cell growth, aging, and the induction of a large number of nuclear genes when cells experience low oxygen levels (Poyton and McEwen, 1996; Castello et al. 2006; Ryan and Hoogenraad, 2007). These effects are brought about by signaling pathways between the mitochondrion and nucleus. Although these pathways are still incompletely understood there is now compelling evidence that superoxide (O2−) nitric oxide (NO), and peroxynitrite (ONOO−) (formed by the reaction of NO with O2−) are involved. The peroxynitrite generated from NO and superoxide is capable of affecting protein tyrosine nitration, which, in turn, may alter specific proteins involved in mitochondrial-nuclear signaling pathways.
In order to better understand and treat disease by photobiomodulation it is important to identify important quantifiable biomarkers that are affected by the disease and subsequently altered by light therapy. This invention provides for these and other needs by disclosing such predictive biomarkers but also in using them to determine the wavelengths of radiation most suitable for phototherapy.